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At least 1,063 records · Page 59
All sourcesNASA NTRSDOE OSTI
DOE OSTI2026

Characterization of Pseudomonas aeruginosa and Acinetobacter calcoaceticus-baumannii complex traumatic wound isolates

Healing of traumatic wounds is complicated by infecting pathogens, with Pseudomonas aeruginosa and members of the Acinetobacter calcoaceticus-baumannii complex among the most common infectious agents. However, a full understanding of genotypic and phenotypic differences between circulating wound isolates is lacking. To address this, traumatic wounds were sampled at Emory University Hospital, and 24 isolates were characterized; we focused on P. aeruginosa and Acinetobacter due to their prevalence and tendency for antibiotic resistance. Even though these species are renowned for antibiotic resistance, only two of the tested isolates could be classified as multidrug resistant. Whole-genome sequencing and analysis revealed that isolates from different patients were genetically distinct; however, longitudinal isolates from the same patient were closely related and appeared to represent chronic colonization by the same strain. Phylogenetic analysis revealed that laboratory strains (PAO1 and AB5075) that were isolated decades previously and from different locations grouped closely to subsets of the recent wound isolates. Given the importance of biofilm formation in infection, the ability of the isolates to form biofilms was assessed; all isolates formed biofilms but showed temporal and magnitude differences. Analysis of a subset of isolates revealed that planktonic P. aeruginosa was resistant to human serum-mediated killing. While the same was true for the majority of Acinetobacter isolates, one showed planktonic sensitivity that was abrogated when grown in a biofilm. Taken together, these data reveal genotypic and phenotypic differences in circulating isolates of P. aeruginosa and A. baumannii.

Acinetobacter↗
DOE OSTI2024

Novel mutation leading to splice donor loss in a conserved site of DMD gene causes Duchenne muscular dystrophy with cryptorchidism

Background As one of the most common congenital abnormalities in male births, cryptorchidism has been found to have a polygenic aetiology according to previous studies of common variants. However, little is known about genetic predisposition of rare variants for cryptorchidism, since rare variants have larger effective size on diseases than common variants. Methods In this study, a cohort of 115 Chinese probands with cryptorchidism was analysed using whole-genome sequencing, alongside 19 parental controls and 2136 unaffected men. Additionally, CRISPR-Cas9 editing of a conserved variant was performed in a mouse model, with MRI screening used to observe the phenotype. Results In 30 of 115 patients (26.1%), we identified four novel genes ( ARSH , DMD , MAGEA4 and SHROOM2 ) affecting at least five unrelated patients and four known genes ( USP9Y , UBA1 , BCORL1 and KDM6A ) with the candidate rare pathogenic variants affecting at least two cases. Burden tests of rare variants revealed the genome-wide significances for newly identified genes (p<2.5×10 −6 ) under the Bonferroni correction. Surprisingly, novel and known genes were mainly found on X chromosome (seven on X and one on Y) and all rare X-chromosomal segregating variants exhibited a maternal inheritance rather than de novo origin. CRISPR-Cas9 mouse modelling of a splice donor loss variant in DMD (NC_000023.11:g.32454661C>G), which resides in a conserved site across vertebrates, replicated bilateral cryptorchidism phenotypes, confirmed by MRI at 4 and 10 weeks. The movement tests further revealed symptoms of Duchenne muscular dystrophy (DMD) in transgenic mice. Conclusion Our results revealed the role of the DMD gene mutation in causing cryptorchidism. The results also suggest that maternal-X inheritance of pathogenic defects could have a predominant role in the development of cryptorchidism.

Chen, Jianhai (ORCID:0000000300932003)↗
DOE OSTI2022

Attention-based Aspect Reasoning for Knowledge Base Question Answering on Clinical Notes

Question Answering (QA) in clinical notes has gained a lot of attention in the past few years. Existing machine reading comprehension approaches in clinical domain can only handle questions about a single block of clinical texts and fail to retrieve information about different patients and clinical notes. To handle more complex questions, we aim at creating knowledge base from clinical notes to link different patients and clinical notes, and performing knowledge base question answering (KBQA). Based on the expert annotations in n2c2, we first created the ClinicalKBQA dataset that includes 8,952 QA pairs and covers questions about seven medical topics through 322 question templates. Then, we proposed an attention-based aspect reasoning (AAR) method for KBQA and investigated the impact of different aspects of answers (e.g., entity, type, path, and context) for prediction. The AAR method achieves better performance due to the well-designed encoder and attention mechanism. In the experiments, we find that both aspects, type and path, enable the model to identify answers satisfying the general conditions and produce lower precision and higher recall. On the other hand, the aspects, entity and context, limit the answers by node-specific information and lead to higher precision and lower recall.

Wang, Ping↗
DOE OSTI2020

The Efficacy and Safety of Mesalamine and Probiotics in Mild‐to‐Moderate Ulcerative Colitis: A Systematic Review and Meta‐Analysis

Objective . To evaluate the efficacy and safety of mesalamine in conjunction with probiotics for ulcerative colitis. Methods . Random controlled trials (RCTs) were searched in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Wanfang, and VIP (VIP Database for Chinese Technical Periodicals) from inception to October 2019. Methodological quality was assessed by the Cochrane Collaboration tool. The quality of evidence was rated by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Data analysis was carried out in Review Manager 5.3. Results . A total of fifteen studies met the criteria for inclusion. Thirteen studies reported the clinical efficacy, three studies provided data on the clinical symptom scores, two trials reported disease activity index, four studies evaluated endoscopic score, and twelve studies reported adverse events. For ulcerative colitis (UC), mesalamine and probiotics had better clinical efficacy than mesalamine alone (≤8 weeks: RR = 1.12, 95% CI: 1.07–1.18, P < 0.0001; >8 weeks: RR = 1.25, 95% CI: 1.11–1.41, P = 0.0003). On the clinical symptom scores, disease activity index, and endoscopic score, UC patients receiving mesalamine and probiotics had significant difference than patients receiving mesalazine alone (MD = −2.02, 95% CI: −3.28 to −0.76, P = 0.002; MD = −1.20, 95% CI: −1.76 to −0.65, P < 0.001; and MD = −0.42, 95% CI: −0.61 to −0.23, P < 0.0001, respectively). There was no statistically significant difference in adverse events between the two groups (RR = 0.88, 95% CI: 0.54 to 1.43, P = 0.60). Conclusion . Our meta‐analysis results supported that mesalamine and probiotics were effective and safe in treating ulcerative colitis.

Tian, Chunying↗
DOE OSTI2021

Quantile-Dependent Expressivity of Serum Uric Acid Concentrations

“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., serum uric acid) is high or low relative to its distribution. Analyses were performed to test whether serum uric acid heritability is quantile-specific and whether this could explain some reported gene-environment interactions. Methods. Serum uric acid concentrations were analyzed from 2151 sibships and 12,068 offspring-parent pairs from the Framingham Heart Study. Quantile-specific heritability from offspring-parent regression slopes (β OP , h 2 = 2β OP /(1 + r spouse )) and full-sib regression slopes (β FS ,h 2 = {(1 + 8r spouse β FS ) 0.5 - 1}/(2r spouse ) was robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. Results. Quantile-specific h 2 (±SE) increased with increasing percentiles of the offspring’s sex- and age-adjusted uric acid distribution when estimated from β OP (P trend = 0.001): 0.34 ± 0.03 at the 10th, 0.36 ± 0.03 at the 25th, 0.41 ± 0.03 at the 50th, 0.46 ± 0.04 at the 75th, and 0.49 ± 0.05 at the 90th percentile and when estimated from β FS (P trend = 0.006). This is consistent with the larger genetic effect size of (1) the SLC2A9 rs11722228 polymorphism in gout patients vs. controls, (2) the ABCG2 rs2231142 polymorphism in men vs. women, (3) the SLC2A9 rs13113918 polymorphism in obese patients prior to bariatric surgery vs. two-year postsurgery following 29 kg weight loss, (4) the ABCG2 rs6855911 polymorphism in obese vs. nonobese women, and (5) the LRP2 rs2544390 polymorphism in heavier drinkers vs. abstainers. Quantile-dependent expressivity may also explain the larger genetic effect size of an SLC2A9/PKD2/ABCG2 haplotype for high vs. low intakes of alcohol, chicken, or processed meats. Conclusions. Heritability of serum uric acid concentrations is quantile-specific.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma

Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia

Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This finding emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML. We performed a comprehensive analysis utilizing a cohort of ~300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 and diminished sensitivity to the MEK inhibitors (MEKi). We validated this association through loss-of-function and pharmacologic inhibition studies. Further, we deployed global phosphoproteomics and CRISPR/Cas9 screening to identify the mechanism of CCR2-mediated MEKi resistance in AML. Our multifaceted analysis unveiled that CCL2 activates multiple prosurvival pathways, including MAPK and cell-cycle regulation in MEKi-resistant cells. Employing combination strategies to simultaneously target these pathways heightened growth inhibition in AML cells. Both genetic and pharmacologic inhibition of CCR2 sensitized AML cells to trametinib, suppressing proliferation while enhancing apoptosis. These findings underscore a new role for CCL2 in MEKi resistance, offering combination therapies as an avenue to circumvent this resistance. Our study demonstrates a compelling rationale for translating CCL2/CCR2 axis inhibitors in combination with MEK pathway-targeting therapies, as a potent strategy for combating drug resistance in AML. This approach has the potential to enhance the efficacy of treatments to improve AML patient outcomes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma

Abstract T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2–7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

Oncology↗
DOE OSTI2025

A Melanoma Brain Metastasis CTC Signature and CTC:B-cell Clusters Associate with Secondary Liver Metastasis: A Melanoma Brain–Liver Metastasis Axis

Melanoma brain metastasis is linked to dismal prognosis and low overall survival and is detected in up to 80% of patients at autopsy. Circulating tumor cells (CTC) are the smallest functional units of cancer and precursors of fatal metastasis. We previously used an unbiased multilevel approach to discover a unique ribosomal protein large/small subunit (RPL/RPS) CTC gene signature associated with melanoma brain metastasis. In this study, we hypothesized that CTC-driven melanoma brain metastasis secondary metastasis (“metastasis of metastasis” per clinical scenarios) has targeted organ specificity for the liver. We injected parallel cohorts of immunodeficient and newly developed humanized NBSGW (huNBSGW) mice with cells from CTC-derived melanoma brain metastasis to identify secondary metastatic patterns. We found the presence of a melanoma brain–liver metastasis axis in huNBSGW mice. Furthermore, RNA sequencing analysis of tissues showed a significant upregulation of the RPL/RPS CTC gene signature linked to metastatic spread to the liver. Additional RNA sequencing of CTCs from huNBSGW blood revealed extensive CTC clustering with human B cells in these mice. CTC:B-cell clusters were also upregulated in the blood of patients with primary melanoma and maintained either in CTC-driven melanoma brain metastasis or melanoma brain metastasis CTC–derived cells promoting liver metastasis. CTC-generated tumor tissues were interrogated at single-cell gene and protein expression levels (10x Genomics Xenium and HALO spatial biology platforms, respectively). Collectively, our findings suggest that heterotypic CTC:B-cell interactions can be critical at multiple stages of metastasis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure–function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. Here, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. Methods: We performed a comprehensive multiomics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Results: Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Conclusions: Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Exosomes From Induced Pluripotent Stem Cell–Derived Cardiomyocytes Promote Autophagy for Myocardial Repair

Background. Induced pluripotent stem cells and their differentiated cardiomyocytes (iCMs) have tremendous potential as patient-specific therapy for ischemic cardiomyopathy following myocardial infarctions, but difficulties in viable transplantation limit clinical translation. Exosomes secreted from iCMs (iCM-Ex) can be robustly collected in vitro and injected in lieu of live iCMs as a cell-free therapy for myocardial infarction. Methods and Results. iCM-Ex were precipitated from iCM supernatant and characterized by protein marker expression, nanoparticle tracking analysis, and functionalized nanogold transmission electron microscopy. iCM-Ex were then used in in vitro and in vivo models of ischemic injuries. Cardiac function in vivo was evaluated by left ventricular ejection fraction and myocardial viability measurements by magnetic resonance imaging. Cardioprotective mechanisms were studied by JC-1 (tetraethylbenzimidazolylcarbocyanine iodide) assay, immunohistochemistry, quantitative real-time polymerase chain reaction, transmission electron microscopy, and immunoblotting. iCM-Ex measured ≈140 nm and expressed CD63 and CD9. iCM and iCM-Ex microRNA profiles had significant overlap, indicating that exosomal content was reflective of the parent cell. Mice treated with iCM-Ex demonstrated significant cardiac improvement post–myocardial infarction, with significantly reduced apoptosis and fibrosis. In vitro iCM apoptosis was significantly reduced by hypoxia and exosome biogenesis inhibition and restored by treatment with iCM-Ex or rapamycin. Autophagosome production and autophagy flux was upregulated in iCM-Ex groups in vivo and in vitro. Conclusions. iCM-Ex improve post–myocardial infarction cardiac function by regulating autophagy in hypoxic cardiomyoytes, enabling a cell-free, patient-specific therapy for ischemic cardiomyopathy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Plasma proteomic biomarkers of physical frailty in heart failure: a propensity score matched discovery-based pilot study

Background: Physical frailty is highly prevalent in heart failure (HF), but we lack an understanding of the underlying pathophysiology. Proteomics evaluation of plasma samples may elucidate potential mechanisms and biomarkers of physical frailty in HF. We aimed to identify plasma proteomic biomarkers that are differentially expressed between physically frail and non physically frail adults with HF. Methods: This was a secondary analysis of a subset of data and plasma samples from a study of frailty among patients with New York Heart Association (NYHA) Functional Classification I-IV HF. Physical frailty was measured using the Frailty Phenotype Criteria. Propensity score matching was used to match pairs of physically frail (n = 20) vs. non-physically frail (n = 20) patients on clinical characteristics. Plasma samples were processed using a sensitive liquid chromatography mass spectrometry platform, utilizing a multiplexed tandem mass tag-labeled quantitative proteomics approach. Differentially expressed proteins were quantified individually using paired t tests with associated log fold change of 0.3 and Fisher’s combined p values. Results: The sample (n = 40) was 62.8±16.9 years old, 58% female, and 55% NYHA Class III/IV. Proteomics analysis revealed 7 proteins differentially expressed using full differential criteria: matrix metalloproteinase-14 was downregulated in frailty, and copine-1, low affinity immunoglobulin gamma Fc region receptor III-A and III-B, probable non-functional immunoglobulin kappa variable 2D-24, glutathione S-transferase Mu 1, and argininosuccinate lyase were upregulated in frailty. Conclusions: Proteomic biomarkers related to the immune system, stress response, and detoxification were differentially expressed between physically frail and non-physically frail adults with HF.

Biomarkers↗
DOE OSTI2022

Sequentially calibrating a Bayesian microsimulation model to incorporate new information and assumptions

Background: Microsimulation models are mathematical models that simulate event histories for individual members of a population. They are useful for policy decisions because they simulate a large number of individuals from an idealized population, with features that change over time, and the resulting event histories can be summarized to describe key population-level outcomes. Model calibration is the process of incorporating evidence into the model. Calibrated models can be used to make predictions about population trends in disease outcomes and effectiveness of interventions, but calibration can be challenging and computationally expensive. Methods: This paper develops a technique for sequentially updating models to take full advantage of earlier calibration results, to ultimately speed up the calibration process. A Bayesian approach to calibration is used because it combines different sources of evidence and enables uncertainty quantification which is appealing for decision-making. We develop this method in order to re-calibrate a microsimulation model for the natural history of colorectal cancer to include new targets that better inform the time from initiation of preclinical cancer to presentation with clinical cancer (sojourn time), because model exploration and validation revealed that more information was needed on sojourn time, and that the predicted percentage of patients with cancers detected via colonoscopy screening was too low. Results: The sequential approach to calibration was more efficient than recalibrating the model from scratch. Incorporating new information on the percentage of patients with cancers detected upon screening changed the estimated sojourn time parameters significantly, increasing the estimated mean sojourn time for cancers in the colon and rectum, providing results with more validity. Conclusions: A sequential approach to recalibration can be used to efficiently recalibrate a microsimulation model when new information becomes available that requires the original targets to be supplemented with additional targets.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

An evaluation of GPT models for phenotype concept recognition

Clinical deep phenotyping and phenotype annotation play a critical role in both the diagnosis of patients with rare disorders as well as in building computationally-tractable knowledge in the rare disorders field. These processes rely on using ontology concepts, often from the Human Phenotype Ontology, in conjunction with a phenotype concept recognition task (supported usually by machine learning methods) to curate patient profiles or existing scientific literature. With the significant shift in the use of large language models (LLMs) for most NLP tasks, we examine the performance of the latest Generative Pre-trained Transformer (GPT) models underpinning ChatGPT as a foundation for the tasks of clinical phenotyping and phenotype annotation. The experimental setup of the study included seven prompts of various levels of specificity, two GPT models (gpt-3.5-turbo and gpt-4.0) and two established gold standard corpora for phenotype recognition, one consisting of publication abstracts and the other clinical observations. The best run, using in-context learning, achieved 0.58 document-level F1 score on publication abstracts and 0.75 document-level F1 score on clinical observations, as well as a mention-level F1 score of 0.7, which surpasses the current best in class tool. Without in-context learning, however, performance is significantly below the existing approaches. Our experiments show that gpt-4.0 surpasses the state of the art performance if the task is constrained to a subset of the target ontology where there is prior knowledge of the terms that are expected to be matched. While the results are promising, the non-deterministic nature of the outcomes, the high cost and the lack of concordance between different runs using the same prompt and input make the use of these LLMs challenging for this particular task.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

The SEMA3F-NRP1/NRP2 axis is a key factor in the acquisition of invasive traits in in situ breast ductal carcinoma

A better understanding of ductal carcinoma in situ (DCIS) is urgently needed to identify these preinvasive lesions as distinct clinical entities. Semaphorin 3F (SEMA3F) is a soluble axonal guidance molecule, and its coreceptors Neuropilin 1 (NRP1) and NRP2 are strongly expressed in invasive epithelial BC cells. We utilized two cell line models to represent the progression from a healthy state to the mild-aggressive or ductal carcinoma in situ (DCIS) stage and, ultimately, to invasive cell lines. Additionally, we employed in vivo models and conducted analyses on patient databases to ensure the translational relevance of our results. We revealed SEMA3F as a promoter of invasion during the DCIS-to-invasive ductal carcinoma transition in breast cancer (BC) through the action of NRP1 and NRP2. In epithelial cells, SEMA3F activates epithelialmesenchymal transition, whereas it promotes extracellular matrix degradation and basal membrane and myoepithelial cell layer breakdown. Together with our patient database data, these proof-of-concept results reveal new SEMA3F-mediated mechanisms occurring in the most common preinvasive BC lesion, DCIS, and represent potent and direct activation of its transition to invasion. Moreover, and of clinical and therapeutic relevance, the effects of SEMA3F can be blocked directly through its coreceptors, thus preventing invasion and keeping DCIS lesions in the preinvasive state.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Xanthohumol microbiome and signature in adults with Crohn’s disease (the XMaS trial): a protocol for a phase II triple-masked, placebo-controlled clinical trial

Xanthohumol (XN), a bioactive flavonoid from Humulus lupulus with anti-inflammatory properties, has potential benefits for patients with Crohn’s disease (CD), a type of inflammatory bowel disease. We recently completed and published results of a placebo-controlled phase I clinical trial demonstrating the safety and tolerability of 24 mg XN daily for 8 weeks. The present study aims to evaluate the safety and tolerability of the same dose of XN adults with clinically active CD in a placebo-controlled phase II clinical trial. Additional aims will assess the impact of XN on inflammatory biomarkers, platelet function, CD clinical activity, and stool microbial composition. The metabolism of XN will also be evaluated. This article provides a model protocol for consideration in investigations of XN or other natural products in disease states. A triple-masked, randomized, placebo-controlled trial will be conducted in adults with clinically active CD. Participants (n ≤ 32) will be randomized to either 24 mg encapsulated XN per day or placebo and followed for 8 weeks. Throughout the trial, participants will be queried for adverse events. Biomarkers of clinical safety, blood and stool markers of inflammation, platelet function, Crohn’s Disease Activity Index score, stool microbial composition, and XN metabolite profiles in blood, urine, and stool will be assessed every 2 weeks. We describe the protocol for a phase II clinical trial that evaluates the safety and tolerability of XN in adults with active CD, as well as evaluate metabolism and mechanisms that are relevant to CD and other diseases with underlying inflammation and/or gut permeability. The effects of XN on inflammatory biomarkers, platelet function, the microbiota, and multi-omics biomarkers measured in this phase II trial of adults with CD will be compared to the effects of XN in healthy adults in our previous phase I trial. The results of the study will advance the evidence guiding the use of XN in patients with CD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer disease

We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer’s disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. We retrospectively included 150 participants, including 29 bvAD, 28 “typical” amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [ 18 F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvAD bvFTD, area under the curve [AUC] range 0.85–0.91, all p < 0.001). The top-3 for bvAD vs. tAD were amygdalar volume (bvAD>tAD), MRI anterior-DMN-ratios (bvAD<tAD), FDG anterior-DMN-ratios (bvAD<tAD, AUC range 0.71–0.84, all p < 0.05). Subtle frontoinsular hypometabolism and anterior DMN involvement may underlie the prominent behavioral phenotype in bvAD.

59 BASIC BIOLOGICAL SCIENCES↗